JPH0576480B2 - - Google Patents

Description

[Detailed description of the invention]

[Object of the Invention] The present invention relates to novel cefem derivatives useful as antibacterial agents. The compound of the present invention has a substituted thiadiazolyl acetamide group or a substituted thiazolyl acetamide group at the 7-position of the cefem skeleton, and as cephem derivatives having these groups, for example, JP-A-55
-11600, JP-A-55-105689, JP-A-57-
No. 24389, JP-A-57-81493, JP-A-58-4789
No., JP-A-58-41887, JP-A-58-59992, JP-A-51-149296, JP-A-52-102293, JP-A-Sho.
No. 52-116492, JP-A-52-125190, JP-A-54-
Compounds described in publications such as No. 154786 and JP-A-57-192394 are known. However, no compound having a (1-morpholino[4,3-b]pyrazolio)methyl group at the 3-position of its cefem skeleton is known. The present inventors have discovered that a compound having the above-mentioned group at the 3-position has excellent antibacterial activity, and has completed the present invention. Therefore, an object of the present invention is to provide a novel compound useful as an antibacterial agent, a method for producing the same, and its use as an antibacterial agent. [Structure of the invention] The compound of the present invention has the general formula:

It is a 3-cephem derivative represented by the formula [wherein Y is ═CH- or a nitrogen atom, and R is a lower alkyl group] and a non-toxic salt thereof. Examples of the lower alkyl group for R in the above general formula () include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, and sec-butyl. In addition, non-toxic salts of the compound of general formula () include pharmaceutically acceptable salts, such as inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, carbonate, and bicarbonate. Acid salts; organic carboxylates such as maleate, lactate, and tartrate; organic sulfonates such as methanesulfonate, benzenesulfonate, and toluenesulfonate; amino acid salts such as aspartate and glutamate etc. Regarding the steric coordination of the following moiety of the compound of the present invention of general formula (),

[C] There is a syn isomer (Z) and an anti isomer (E). Although both isomers are included in the present invention, the syn isomer is preferred from the standpoint of antibacterial activity. The compound of the present invention can be produced by the method shown below. general formula

[Chemical Formula] [In the formula, Y and R are the same as defined above], a compound whose functional group is protected with a protecting group, or a salt thereof, has the formula:

The compound represented by the formula () or a non-toxic salt thereof can be obtained by reacting the compound represented by the formula (I) or its salt. The above reaction can be carried out by a conventional method. For example, it can be carried out in the presence of an alkali metal salt. Examples of alkali metal salts include sodium iodide, potassium iodide, sodium bromide, potassium bromide, sodium thiocyanate, potassium thiocyanate, and sodium nitrate. The reaction solvent used in this case may be an aqueous solvent such as water or a buffer solution, a hydrophilic solvent such as formamide, N,N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, propionitrile, methanol, or a mixed solvent thereof. Can be used. A suitable reaction temperature is 30°C to 90°C. Alternatively, the reaction can be carried out in the presence of a halogenating agent, such as iodotrimethylsilane. This reaction begins with the general formula ()
A compound of formula (), a compound whose functional group is protected with a protecting group, or a salt thereof is treated with a halogenating agent, and then a compound of formula () or a salt thereof is reacted.
As a reaction solvent, lower alkyl nitriles such as acetonitrile and propionitrile; lower alkyl halides such as methane chloride, methylene chloride, and chloroform; ethers such as tetrahydrofuran and dioxane; amides such as N,N-dimethylformamide; acetic acid Esters such as ethyl;
Examples include ketones such as acetone; hydrocarbons such as benzene; and mixed solvents thereof. A suitable reaction temperature is -40°C to 60°C. As the salt of the compound of general formula () and formula () and the protective group for the functional group, commonly used ones can be used as long as they do not interfere with the above reaction. For example, protective groups for amino groups include formyl, dichloroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, trityl, p-
Methoxybenzyl, benzhydryl, etc.; Protecting groups for carboxyl groups include p-methoxybenzyl, p-nitrobenzyl, t-butyl, methyl,
Examples include 2,2,2-trichloroethyl, benzhydryl, pivaloyloxymethyl, and the like.
Also, bis(trimethylsilyl)acetamide,
If a silylating agent such as N-methyl-N-trimethylsilyl-acetamide or N-methyl-N-trimethylsilyl-trifluoroacetamide is used, amino groups and carboxyl groups can be protected at the same time. In addition, the salts of the compounds of general formula () and formula () include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; hydrochlorides, bromide salts, etc. Inorganic acid salts such as hydrates, sulfates, carbonates, hydroiodides, bicarbonates; organic carbonates such as acetates, trifluoroacetates, trichloroacetates, maleates, lactates, tartrates, etc. Acid salts: Organic sulfonates such as methanesulfonate, benzenesulfonate, toluenesulfonate; trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzyl Ethylenediamine salt, triethanolamine salt,
Examples include amine salts such as tris(hydroxymethylamino)methane salt and phenethylbenzylamine salt; amino acid salts such as arginine salt, aspartate, lysine salt, glutamate, and serine salt. The compounds of the present invention exhibit strong antibacterial activity against Gram-positive and Gram-negative bacteria. In addition, the acute toxicity value [LD ₅₀ (mouse, intravenous injection)] is 5 for the following compounds.
g/Kg or more. 7β-[2-(2-aminothiazol-4-yl)
-2-(Z)-methoxyiminoacetamide]-3
-(1-morpholino[4,3-b]pyrazolio)
Methyl-3-cephem-4-carboxylate 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z)-methoxyiminoacetamide]-3-(1-morpholino [4,3
-b]pyrazolio)methyl-3-cephem-4-
Carboxylate When the compound of the present invention is used as an antibacterial agent, the dosage is 2 to 300 mg/Kg/day, preferably 10 to 100 mg/Kg/day.
mg/Kg/day. The antibacterial agent is administered orally in the form of powders, granules, capsules, tablets, etc., or parenterally in the form of injections, suppositories, etc. These preparations can be manufactured by conventional methods using pharmaceutically acceptable carriers. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples. Example 1 7β-[2-(2-aminothiazol-4-yl)
-2-(Z)-methoxyiminoacetamide]-3
-(1-morpholino[4,3-b]pyrazolio)
Methyl-3-cephem-4-carboxylate

[Chemical] 7β-[2-(2-aminothiazol-4-yl)
-2-(Z)-methoxyiminoacetamide]-3
-acetoxymethyl-3-cephem-4-carboxylic acid 1200 mg, morpholino[4,3-b]pyrazole 600 mg, sodium iodide 4.8 g and water 2.4 ml
The mixture was stirred at 60°C for 3 hours. Add 100ml of acetone to the reaction solution, remove the resulting precipitate,
Purification was performed by reverse phase silica gel chromatography to obtain 70 mg of the desired product. Infrared absorption spectrum (cm ^-1 , Nujiol):
1770, 1660, 1610 NMR spectrum (δ, DMSO−d ₆ ): 3.8 (3H,
s), 4.1-4.3 (2H, m), 4.3-4.5 (2H, m),
4.95 (2H, s), 5.02 (1H, d, J=5Hz),
5.1~5.6 (2H, m), 5.6 (1H, dd, J=5Hz,
10Hz), 6.7 (1H, s), 6.71 (1H, d, J=2
Hz), 7.17 (2H, brs), 8.50 (1H, d, J=2
Hz), 9.50 (1H, d, J = 10Hz) Example 2 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z)-methoxyiminoacetamide]- 3-(1-morpholino[4,3
-b]pyrazolio)methyl-3-cephem-4-
carboxylate

[Chemical formula] 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z)-methoxyiminoacetamide]-3-acetoxymethyl-3-
A mixture consisting of 600 mg of cefem-4-carboxylic acid, 300 mg of morpholino[4,3-b]pyrazole, 2.4 g of sodium iodide, and 1.2 ml of water was stirred at 60°C for 2 hours. 50 ml of acetone was added to the reaction solution and the resulting precipitate was collected. This was purified by reverse phase silica gel chromatography to obtain 70 mg of the desired product. Infrared absorption spectrum (cm ^-1 , Nujiol):
1770, 1660, 1610 NMR spectrum (δ, DMSO−d ₆ ): 3.98 (3H,
s), 4.1-4.3 (2H, m), 4.3-4.5 (2H, m),
4.94 (2H, s), 5.01 (1H, d, J=5Hz),
5.22 (1H, d, J = 16Hz), 5.51 (1H, d, J
= 16Hz), 5.61 (1H, dd, J = 5Hz, 10Hz),
6.72 (1H, d, J=2Hz), 8.12 (2H, brs),
8.50 (1H, d, J = 2Hz), 9.50 (1H, d, J
=10Hz) [Effects of the invention]

[Table] * β-lactamase producing bacteria

Claims (1)

[Scope of Claims] 1. A 3-cephem derivative represented by the general formula: [In the formula, Y is =CH- or a nitrogen atom, and R represents a lower alkyl group] and a non-toxic salt thereof. 2. The compound according to claim 1, wherein R is a methyl group. 3 A compound represented by the formula and its non-toxic salt,
A compound according to claim 1. 4 A compound represented by the general formula [Chemical formula] [In the formula, Y is =CH- or a nitrogen atom, R represents a lower alkyl group], a compound whose functional group is protected, or a salt thereof, with the formula [Chemical formula] 1. A method for producing a compound represented by the general formula: [Formula (2), wherein Y and R are as defined above] or a non-toxic salt thereof, which comprises reacting the represented compound or a salt thereof. 5. An antibacterial agent comprising a compound represented by the general formula: [In the formula, Y is =CH- or a nitrogen atom, and R represents a lower alkyl group] or a non-toxic salt thereof.